Pharmacological activation of p53 induces dose-dependent changes in endothelial cell fate during angiogenic sprouting
(2025) In Cell Death and Disease 16(1).- Abstract
The cell cycle is a key regulator of endothelial cell specification into tip and stalk cell phenotypes, which are essential for angiogenesis in both normal development and pathological conditions. While the tumor suppressor p53 is known to regulate the cell cycle and influence cell fate, its role in modulating the cell fate of these phenotypes remains unclear. Using non-genotoxic small molecule and stapled peptide compounds to pharmacologically activate p53 via MDM2 inhibition, we demonstrate that graded levels of p53 induce distinct cellular fates in normal endothelial cells. Low levels of p53 induce reversible cell cycle arrest by reducing DNA replication, while high levels induce senescence and cell death. Surprisingly, all tested... (More)
The cell cycle is a key regulator of endothelial cell specification into tip and stalk cell phenotypes, which are essential for angiogenesis in both normal development and pathological conditions. While the tumor suppressor p53 is known to regulate the cell cycle and influence cell fate, its role in modulating the cell fate of these phenotypes remains unclear. Using non-genotoxic small molecule and stapled peptide compounds to pharmacologically activate p53 via MDM2 inhibition, we demonstrate that graded levels of p53 induce distinct cellular fates in normal endothelial cells. Low levels of p53 induce reversible cell cycle arrest by reducing DNA replication, while high levels induce senescence and cell death. Surprisingly, all tested levels of p53 activation reduced the growth of venous blood vessels in vitro and in zebrafish embryo models. This reduction in sprouting may stem from distinct cellular responses in tip-like and non-tip-like cells to pharmacological p53 activation: low p53 levels primarily reduced proliferation in non-tip-like cells, whereas high levels decreased the frequency of tip-like cells and the expression of genes associated with tip and stalk cell identities. Our findings show for the first time that pharmacological p53 activation modulates endothelial cell fate in a dose-dependent manner during sprouting angiogenesis. They also highlight the potential of using graded p53 modulation as a therapeutic strategy to target abnormal tip or stalk cell development in pathological angiogenesis, such as in cancer.
(Less)
- author
- Al-Radi, Omayma
; Ingelshed, Katrine
; Eichhorn, Lisa
; Josefsson, Heidi
; Krkoska, Martin
; Bräutigam, Lars
; Lindström, Susanne
; Végvári, Ákos
; Kheder, Sania
; Cerrato, Carmine P.
; Fermé, Suzon
; Bosdotter, Cecilia
; Allalou, Amin
; Levander, Fredrik
LU
; Vojtesek, Borivoj
; Lane, David P.
and Kannan, Pavitra
(Less) - organization
- publishing date
- 2025-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Death and Disease
- volume
- 16
- issue
- 1
- article number
- 883
- publisher
- Springer Nature
- external identifiers
-
- scopus:105024712487
- pmid:41360924
- ISSN
- 2041-4889
- DOI
- 10.1038/s41419-025-08292-7
- language
- English
- LU publication?
- yes
- id
- 4f721f94-69ad-434a-9ebe-50d0c37cc29b
- date added to LUP
- 2026-02-13 10:38:00
- date last changed
- 2026-02-14 03:00:08
@article{4f721f94-69ad-434a-9ebe-50d0c37cc29b,
abstract = {{<p>The cell cycle is a key regulator of endothelial cell specification into tip and stalk cell phenotypes, which are essential for angiogenesis in both normal development and pathological conditions. While the tumor suppressor p53 is known to regulate the cell cycle and influence cell fate, its role in modulating the cell fate of these phenotypes remains unclear. Using non-genotoxic small molecule and stapled peptide compounds to pharmacologically activate p53 via MDM2 inhibition, we demonstrate that graded levels of p53 induce distinct cellular fates in normal endothelial cells. Low levels of p53 induce reversible cell cycle arrest by reducing DNA replication, while high levels induce senescence and cell death. Surprisingly, all tested levels of p53 activation reduced the growth of venous blood vessels in vitro and in zebrafish embryo models. This reduction in sprouting may stem from distinct cellular responses in tip-like and non-tip-like cells to pharmacological p53 activation: low p53 levels primarily reduced proliferation in non-tip-like cells, whereas high levels decreased the frequency of tip-like cells and the expression of genes associated with tip and stalk cell identities. Our findings show for the first time that pharmacological p53 activation modulates endothelial cell fate in a dose-dependent manner during sprouting angiogenesis. They also highlight the potential of using graded p53 modulation as a therapeutic strategy to target abnormal tip or stalk cell development in pathological angiogenesis, such as in cancer.</p>}},
author = {{Al-Radi, Omayma and Ingelshed, Katrine and Eichhorn, Lisa and Josefsson, Heidi and Krkoska, Martin and Bräutigam, Lars and Lindström, Susanne and Végvári, Ákos and Kheder, Sania and Cerrato, Carmine P. and Fermé, Suzon and Bosdotter, Cecilia and Allalou, Amin and Levander, Fredrik and Vojtesek, Borivoj and Lane, David P. and Kannan, Pavitra}},
issn = {{2041-4889}},
language = {{eng}},
number = {{1}},
publisher = {{Springer Nature}},
series = {{Cell Death and Disease}},
title = {{Pharmacological activation of p53 induces dose-dependent changes in endothelial cell fate during angiogenic sprouting}},
url = {{http://dx.doi.org/10.1038/s41419-025-08292-7}},
doi = {{10.1038/s41419-025-08292-7}},
volume = {{16}},
year = {{2025}},
}